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Acta Pharmaceutica Sinica B 2013;3(3):150–153 Institute of Materia Medica, Chinese Academy of Medical Sciences Chinese Pharmaceutical Association Acta Pharmaceutica Sinica B www.elsevier.com/locate/apsb www.sciencedirect.com REVIEW Repolarization reserve, arrhythmia and new drug development Yang Lin, Yicheng Fu Institute of Geriatric Cardiology, the Chinese PLA General Hospital, Beijing 100853, China Received 25 December 2012; revised 15 February 2013; accepted 22 February 2013 KEY WORDS Repolarization reserve; Ion channels; Arrhythmias; QT prolongation; Drug development strategy Abstract Repolarization-related lethal arrhythmias have led to the concept of “repolarization reserve”, which may help elucidate the relationship between Kþ currents and other components of repolarization. Pharmacological manipulation as well as congenital and cardiac disease may affect repolarization and alter the repolarization reserve, leading to the development of arrhythmias. Pharmacological enhancement of outward currents or suppression of inward currents has been shown to be of therapeutic value. A number of newly found selective ion channel inhibitors or agonists have been investigated for their ability to enhance repolarization reserve and decrease the incidence of arrhythmia. In this paper we review the development, potential mechanisms, clinical application, and pharmacological significance of repolarization reserve in order to better understand, predict and prevent unexplained adverse cardiac events. & 2013 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved. n Corresponding author. Tel.: þ86 10 6693 6762. E-mail address: [email protected] (Yang Li). Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. 2211-3835 & 2013 Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.apsb.2013.03.001 Repolarization reserve, arrhythmia and new drug development 1. Introduction Enhanced variability in cardiac repolarization has been linked to increased arrhythmic risk in both experimental and clinical studies. Clinicians have found that some drugs producing minimal QT prolongation in one patient may cause significant QT prolongation or torsade de pointes (TdP) in the other patients1. The causes of spatio-temporal cardiac repolarization variability are still under investigation. The term “repolarization reserve” was first raised by Roden in 19982. After 10 years, repolarization reserve has been defined by Roden again as following3: “Loss of one component (such as rapidly delayed rectified potassium currents, IKr) ordinarily will not lead to failure of repolarization (i.e., marked QT prolongation); as a corollary, individuals with subclinical lesions in other components of the system, say slowly delayed rectified potassium currents (IKs) or calcium current, may display no QT change until IKr block is superimposed.” This suggests that other Kþ currents are compensatorily increased when dysfunction or inhibition of one Kþ current occurs, so that changes in action potential duration (APD) are minimized. It has proposed that pathologic factors contributing to dysfunction of repolarization reserve would bring not only excessive APD prolongation but lethal arrhythmias by mild blockade of potassium channels4. The repolarization reserve concept seems to be a new approach for clinicians to better understand adverse drug reactions, cardiac repolarization and arrhythmias. 2. Ion mechanism of repolarization reserve It is thought that subtle interactions of multiple ion channels govern the repolarization process of cardiac myocytes. A major mechanism contributing to repolarization reserve is IKr and IKs. At the ionic level, IKs is an important determinant of ventricular repolarization. Although IKs may have little role in APD under physiologic conditions, it probably plays a vital role when APD is abnormally prolonged by reduction of outward currents or enhancement of inward currents induced by drug usage, hypokalaemia, genetic abnormality and bradycardia5. The subsequent prolongation in APD would result in IKs activation and exert negative feedback to further APD prolongation. IKr is not only a main outward current determining repolarization but itself is clearly the most important contributor to repolarization reserve. Studies have demonstrated that reductions in IKr may lead to compensatory up-regulation of IKs. Xiao et al.6 reported that adult canine left ventricular cardiomyocytes treated with dofetilide for 24 h developed APD shortening and enhancement of repolarization reserve, which was accompanied by increased IKs density. Dofetilide had no significant effect on mRNA expression corresponding to KCNH2 (potassium voltage-gated channel subfamily H member 2) and KCNE2 (potassium voltage-gated channel subfamily E member 2) for IKr or KCNQ1 (potassium voltagegated channel KQT-like subfamily member 1) and KCNE1 for IKs, but increased protein expression of KvLQT1 and KCNE1. The expression levels of the muscle-specific microRNA subtypes miR133a and miR-133b were significantly reduced in the dofetilide group compared with the control group, suggesting that the compensatory upregulation of IKs was achieved through posttranscriptional regulation, and was closely associated with microRNA changes. IKs gating mechanisms responsible for the change of repolarization reserve is gradually becoming elucidated. The closed states of the gating channel play a key role in IKs current 151 change. In 2003, Silverman provided a hypothesis that IKs has two closed states. The second closed state must arise from first state via a slow transition phase7. It is recognized that 40% of the channels were in first closed state at low heart rates and 60% of the channels were in first closed state at high heart rates. At high heart rates, more first-closed channels contribute to repolarizing reserve. IKs has a reserve of channels in the closed state that can open rapidly to generate current at fast rate (rate-adaptation), preventing excessive APD prolongation and proarrhythmia6,8. It recently has been reported that other currents also contribute to repolarization reserve. Several studies indicated that late sodium current (INa,L) was up-regulated by various factors and represented a functional reserve under disease conditions. Augmentation of INa,L by gene mutations or polymorphisms and drugs opposes outward currents and impairs repolarization reserve. Enhancement of INa,L has been shown to elicit delayed after-depolarization and induce long QT3(LQT3) syndrome and other arrhythmias. Studies showed that drug-induced reduction of INa,L in cardiomyocytes isolated from ischemic myocardium exposed to oxidative stress is closely related to cardiac electrical activity9,10. Surprisingly and interestingly, the hyperpolarization activity current (If), which contributes to the pacemaker current in the sinus node, also affects repolarization reserve. Hofmann et al.11 reported the notable increase of HCN1 (potassium/sodium hyperpolarizationactivated cyclic nucleotide-gated channel 1) in the hypertrophic ventricle, while low levels of HCN1 are expressed under normal physiological conditions. HCN channel activity, as an inward current, can contribute to action potential repolarization. Moreover, blockade of ventricular HCN current by drugs improves the repolarization reserve and helps to maintain electrical stability in cardiac disease states, as evidenced by the beneficial effect of the Ifblock erivabradine on heart failure12. The inward sarcolemmal NCX current might significantly reduce the function of repolarization reserve in calcium overloads and induce early (EADs) and delayed after-depolarization (DADs). Consequently, the vulnerability to arrhythmias is increased13. SEA0400, with its acute inhibition of NCX, prevents polymorphic VTs in experimental models of long QT2 (LQT2) syndrome and LQT3, improving repolarization reserve and reducing the burden of proarrhythmia14. 3. Repolarization reserve and arrhythmias To better understand the relationship between repolarization reserve and arrhythmias, a unifying framework for understanding their relationship to cardiac repolarization is provided15. Inherited arrhythmias result from mutations in genes encoding cardiac ion channels, cytoskeletal anchoring proteins and components of caveolae. In contrast, acquired arrhythmias are induced through blockade of IKr by many cardiac and non-cardiac drugs. Other risk factors that may contribute to ionic disturbances include gender and cardiac pathology. The interplay of the above factors determines the repolarization reserve capacity. Attenuation of the repolarization reserve due to drugs, remodeling, or genetic disorders may lead to prolonged repolarization and development of lethal arrhythmia under certain conditions. In the clinical setting, reduction of repolarization reserve has been associated with an increased risk of arrhythmogenesis in patients with inherited LQTs and/or structural heart disease. Repolarization reserve might be further diminished by concomitant drug therapy and a variety of conditions such as hypokalemia 152 and bradycardia. Electrophysiological remodeling of ion channels in heart failure leads to prolongation of APD and decreased repolarization reserve, incorporating down-regulated IKs and upregulated INCX and INa,L13,16. Excessive prolongation of APD and impairment of repolarization reserve will lead to arrhythmogenic after-depolarizations, especially EADs, with triggering complex re-entry. Guo et al.17 found by pharmacologic manipulation that IKs becomes the main repolarization current rather than IKr in early reperfusion. A drug-induced blockade of IKs in this situation led to an increase in ventricular arrhythmias, which was a consequence of impairment of the repolarization reserve. The mechanism by which impairment of repolarization reserve develops into arrhythmia is still masked. According to a theory introduced by Varró18, lengthening of repolarization and decreased repolarization reserve lead to enhanced spatial repolarization heterogeneity. This hypothetical mechanism suggests that the effective refractory period (ERP) is significantly shorter than the APD in normal conditions. The cells are resistant to early stimulation because they are in a refractory state. However, in pathologic circumstances, ERP is prolonged and the repolarization heterogeneity is augmented by repolarization reserve impairment. Consequently, a premature beat stimulus can travel back to its origin due to enhanced differences in refractoriness of different heart regions, leading to ventricular arrhythmias. According to this concept, distribution in mid-myocardium of IKs is much less than in the epicardium, which likely leads to a greater prolongation of APD in the mid-myocardium by the IKs blocker, thereby increasing transmural repolarization-dispersion (TRD) and inducing arrhythmias. In contrast, a greater distribution of INa in endocardial rather than epicardial tissue allows a greater prolongation of ERP in the endocardium by the INa blocker and reduces ERP dispersion, exerting an antiarrhythmic effect. 4. Repolarization reserve and new drug development strategy Unexpected induction of arrhythmias in the heart is still one of the major risks of new drugs despite recent improvements in cardiac safety assays. The major adverse effects of drugs have been associated with decreased cardiac repolarization reserve. The drugs may not cause significant APD lengthening under normal conditions, but in patients with impaired repolarization reserve, the risk for excessive APD prolongation and arrhythmia are greatly enhanced. Therefore, the preclinical safety pharmacology screenings should be extended to preparations in which repolarization reserve is modified. Therapeutically, there are several basic options to enhance repolarization reserve and decrease the risk of proarrhythmia. Firstly, it would be beneficial to inhibit inward sodium and calcium currents, and to increase more than one outward potassium currents would also be advisable, which is expected to have much less proarrhythmic risk than selective potassium channel inhibitors. The best candidate in this case is amiodarone. As one of the most effective selective potassium channels blockers, amiodarone also inhibits both INa and ICa,L, substantially lengthening repolarization. Its proarrhythmic effect is consequently much less significant than other class III antiarrhythmics which inhibit only potassium channels19. Recently, dronedarone, a modified analogue of amiodarone which inhibits Naþ, Ca2þ and NCH4 channels, has drawn great attention for its ability to maintain sinus rhythm and terminate a trial fibrillation20. Vernakalant may affect several ion channels expressed in atrium Yang Li, Yicheng Fu myocytes and protect against Naþ channel blockade21. Secondly, as a negative feedback mechanism, enhancement of Kþ currents would limit repolarization prolongaton. A recent study on repolarization reserve indicated that pharmacological activation of IKs enhances antiarrhythmic characteristics and counteracts IKr reduction6. The benzodiazepine L-364,373(R-L3) stimulates IKs activation, compensates for repolarization impairment due to reduced IKr, and decreases QT variability and the occurrence of extrasystoles in the heart failure22. hERG channel agonists, NS-3623 and NS-1643, were found to enhance IKr and limit QT prolongation in experimental animal models23,24. ATP-sensitive potassium channel (KATP) openers, nicorandil, pinacidil and diazoxide, suppress EADs and decrease the incidence of premature ventricular contractions25,26. SNC-80, selectively activating the deltaopioid receptor, subsequently opens KATP channels and provides cytoprotection and antiarrhythmic protection against hypoxia reoxygenation effects27. Lastly, the development of new drug should evaluate their effect on repolarization heterogeneity. Studies indicate that impairment in repolarization reserve elicits TdP by increasing repolarization heterogeneity and triggered activity28. The difference between the APD and the ERP of adjacent cells is very small under normal conditions. However, repolarization heterogeneities would be amplified and repolarization reserve would be reduced with the usage of pro-arrhythmic cardiac and non-cardiac drugs under pathologic conditions, which could dramatically increase the incidence of lethal arrhythmias18. As a new concept, repolarization reserve explains the interaction of multiple currents contributing to cardiac reserve function. Accordingly, inhibition or functional impairment of one ion channel does not lead to prolongation of repolarization owing to compensation from other currents. Currently, most research on mechanisms of repolarization reserve use only isolated cardiomyocytes. The cardiac action potential represents the integrated activity of dozens or hundreds of individual components of ion currents, and the behavior of these individual components generates and affects the action potential. 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